Erythromycin A is an antibiotic which has been widely used as a therapeutic agent for infectious diseases caused by Gram-positive bacteria, mycoplasmas, and the like. However, due to decomposition by gastric acid, erythromycin has a drawback of inconstant pharmacokinetics. Therefore, derivatives of erythromycin having increased stability to acids were researched. As a result, macrolides having stable pharmacokinetics such as clarithromycin, azithromycin (Patent documents 1 and 2) and roxithromycin have been developed. These macrolide agents have been applied in a therapeutic field of respiratory infectious diseases of ambulatory patients, and therefore, they are required to have a potent antibacterial activity especially against pneumococci, streptococci, and Hemophilus influenzae which are frequently isolated clinically. Furthermore, since macrolide-resistant pneumococci have been highly frequently isolated from community acquired pneumonia patients, it has been considered important that they are effective against the resistant pneumococci.
As a result of various researches in recent years, Agouridas et al. found HMR3647 (telithromycin, Patent document 3) in 1995, and successively Or et al. found ABT-773 (cethromycin, Patent document 4) in 1998 as macrolides that are effective both against erythromycin resistant pneumococci and erythromycin resistant streptococci. Then, 2-fluoroketolide (Patent document 5) of which efficacy was further enhanced was reported.
From a structural viewpoint, marketed macrolides are mainly classified into 14-membered or 15-membered ring type macrolides which are erythromycin derivatives, and 16-membered ring type macrolides which are leucomycin derivatives. Among the erythromycin derivatives, the 15-membered ring macrolides include azithromycin mentioned above. Azithromycin, unlike the other 14-membered ring macrolides, possesses a structural feature of having a nitrogen atom in the lactone ring, and therefore the macrolide is called azalide. Nomenclature of azalides is based on the position number of a carbon atom substituted with a nitrogen atom when the carbonyl group of the lactone is assumed to be in the 1-position. In the case of azithromycin mentioned above, since the nitrogen atom is introduced in the position of the ninth carbon atom from the carbonyl group, the compound is called 9a-azalide.
In addition to the 9a-azalides, 8a-azalides (Patent document 6) and 11a-azalides (Patent document 7) are known as examples of reported azalides obtainable by chemical conversion of 14-membered ring macrolides.
As for 10a-azalides, those derived from 16-membered ring macrolides as leucomycin derivatives have recently been reported (Patent document 8). However, no 10a-azalides derived from 14-membered ring macrolides have been reported. Although 10a-azalides are disclosed in Patent document 9, which was published after the priority date of the present international application (Aug. 6, 2007), this publication does not constitute a prior art of the present invention.    Patent document 1: U.S. Pat. No. 4,474,768    Patent document 2: U.S. Pat. No. 4,517,359    Patent document 3: EP680967    Patent document 4: WO98/09978    Patent document 5: WO02/32919    Patent document 6: EP508726    Patent document 7: WO2003/014136    Patent document 8: WO2005/019238    Patent document 9: WO2007/091393